The long term goals of this project are to contribute to the chemistry and biochemistry of conceptually novel nucleosides, nucleotides and related analogs and derivatives with useful therapeutic potential against the infectivity of the human immunodeficiency virus (HIV). The specific aims of this project are the design, synthesis, enzymology and anti-HIV studies of a new family of structurally and stereochemically defined compounds that are isomeric with the natural nucleosides and nucleotides and that are referred to as isonucleosides and isonucleotides. A potently anti-HIV active isodideoxynucleoside [4(S)-(6-amino-9H-purin-9-yl)tetra- hydro-2(S)-furanmethanol, (S,S)-IsoddA] has been discovered in the current grant project. IsoddA as its 5'-triphosphate is also a very strong inhibitor of the viral enzyme, HIV reverse transcriptase. This renewal proposal seeks: (1) to continue the successful work of the current project on conceptually new isonucleosides and their phosphorylated derivatives as potential anti-HIV agents and inhibitors of HIV reverse transcriptase; (2) to investigate a new series of strategically modified isonucleotides as potential inhibitors of another key viral enzyme, HIV integrase. The synthetic work proposed will involve the development of approaches to optically active novel isodideoxynucleosides and isodideoxynucleotides and their purification and complete characterization by NMR, FAB and electrospray mass spectrometry, and X-ray crystallography. Collaborative antiviral studies on the target compounds and pro-drug forms will be carried out against HIV-1 and HIV-2, including drug-resistant HIV isolates. Data on inhibition of the cytopathic effect of HIV, on inhibition of HIV RT, on inhibition of HIV integrase-catalyzed reactions, on inhibition of integrase-DNA binding, on inhibition of proviral DNA synthesis, on host cell cytotoxicity including inhibition of cellular DNA polymerases alpha, beta and gamma on therapeutic indexes will be determined and analyzed. Cellular combination drug studies, particularly those having the potential for synergistic inhibition of HIV infectivity, are also planned.